Pervasive Developmental Disorder (PDD) is a category of extremely debilitating behavioral disorder of childhood which includes autism, and for whom efficacious therapy is lacking. Neuroleptic use in PDD is high even in children as young as 2 years. The PDD population appears to be particularly vulnerable and at increased risk of serious sequelae including extrapyramidal side effects (EPS) and tardive dyskinesia. An atypical neuroleptic risperidone (RIS) is now used in 87 percent of pediatric cases, but pharmacokinetic (PK) and safety data are lacking in this vulnerable population. Our laboratory has recently explored the relationship between the inter-individual metabolism of RIS and EPS. Recent evidence suggests that the major active metabolite of RIS, 9-hydroxyrisperidone (9-OH-RIS) is present in enantiomeric forms with potentially differing toxic profiles. This metabolic finding, coupled with the lack of basic PK information in children with PDD, suggests further study is needed to promote better dose titration and safety in the clinical use of RIS. Our research plan is to: (1) adapt and establish assay methodology sufficient for pediatric sampling; (2) prove feasibility of RIS and 9-OH-RIS enantiomers determination in samples from pediatric PDD patients; (3) gather preliminary population PK data sufficient to provide parameter estimates to allow future full population PK characterization in children suffering from PDD, and explore the relationship between EPS adverse event data and RIS metabolism/ elimination. We propose a collaborative multi-center approach utilizing the complementary strengths of two NIH supported Pediatric Pharmacology Networks; i.e. the Pediatric Pharmacology Research Unit (PPRU) (lead site Cincinnati Children's) and the Research Units of Pediatric Psychopharmacology (RUPP) networks (lead site Ohio State). This strategy will rely on the unique strengths and expertise of each network to collaboratively produce innovative technology and apply it to a vulnerable population to achieve maximum public health benefit. The RUPP network is able to access PDD patients and optimize clinical sampling while the PPRU network has expertise in micro-assay development and access to a GLP certified lab (Louisiana State University) as well as population PK expertise (Cincinnati and San Diego). Specifically, we plan a population PK study in which we will determine drug concentration-time profiles of RIS by integrating information from relatively dense data, absorption phase levels through the early and late hours of drug elimination, with a sparse sampling strategy. The population approach will allow the analysis of data from ongoing clinical trials as well as from a study specifically designed for PK evaluation. RIS and 9-OH-RIS enantiomeric concentrations will be determined with a new low volume high sensitivity assay. Simultaneously we will survey therapeutic plasma concentrations of RIS and 9-OH-RIS enantiomers, characterize pharmacodynamic RIS and 9-OH-RIS enantiomers (e.g. EPS), and obtain safety/adverse event data.